Fiber type
Local anesthetic sensitivity
Size
Myelination
A
+
Large
Yes
B
++
Medium
Yes
C
+++
Small
No
pH: Most local anesthetics are weak bases that exist as an equilibrium of a more lipid soluble, neutral form and a less lipid soluble, charged form. The local anesthetics typically have pKa’s greater than 7.4, so less than 50 % of the drug exists in the lipid soluble form in normal extracellular fluid. Additionally, commercial preparations of local anesthetics typically have pH’s between 6 and 7, further increasing the proportion of the drug in the protonated form. The action of local anesthetics requires that their molecules permeate lipid-rich neural membranes to reach their site of action. Clinical implications of these factors are:
Addition of sodium bicarbonate to the local anesthetic solution (typically 1 ml of sodium bicarbonate solution to 10 ml of local anesthetic) increases pH and the fraction of local anesthetic in neutral form, speeding onset of action.
Tissues with local acidosis (e.g., infected or ischemic tissues) will be relatively resistant to local anesthetic action.
Use-dependent blockade: Access to sodium channels is enhanced by repeated membrane depolarization because depolarization increases the time that the channels spend in the open or inactivated forms. Frequent action potentials in the presence of local anesthetic speeds onset of neural blockade.
Epinephrine: Epinephrine affects local anesthetic action in two ways:
Epinephrine-containing local anesthetic solutions are formulated at lower pH’s (4–5) than plain local solutions because of epinephrine’s instability in alkaline environments. Low pH slows onset of local anesthetic action as described above.
Epinephrine causes local vasoconstriction and slows absorption of the local anesthetic from its site of deposition, prolonging local anesthetic action. This effect is prominent with the shorter-acting local anesthetics (e.g. lidocaine blockade can be increased 50 % by addition of epinephrine). The longer-acting local anesthetics (bupivacaine and ropivacaine) are released so slowly from neural tissue that epinephrine does not significantly increase their durations of blockade, but does decrease their peak blood concentrations after injection.
Local Anesthetic Metabolism
The action of local anesthetics is terminated by absorption of the drug from the site of action into the circulation. Following absorption, the drug is metabolized and excreted.
Local anesthetics fall into two structural categories, amides and esters. A schematic representation of local anesthetic structure is shown in Fig. 6.1.
Figure 6.1
Local anesthetic structure
Amides are metabolized by microsomal enzymes (cytochromes) in the liver
Esters are primarily metabolized by pseudocholinesterase in the plasma (the exception is cocaine, which is partially metabolized by the liver and partially excreted unchanged by the kidneys)
Peak blood levels of local anesthetics are related to the dose administered and the rate of absorption of the drug from its site of action. Injection into a highly vascular area leads to higher blood levels of the drug than placing a similar amount of drug into a less vascular area. The rank order of peak blood concentrations of local anesthetic after administration of the same dose of drug at different sites is shown below:
intravenous > tracheal > intercostal > caudal > epidural > brachial plexus > sciatic > subcutaneous injection
Epinephrine and other vasoconstrictors slow the rate of absorption.
Strongly protein-bound local anesthetics (e.g. bupivacaine and ropivacaine) tend to be more lipid soluble, more potent, and have longer times to onset, longer durations of action, and slower absorption from neural tissue (Table 6.2).
Table 6.2
Properties of common local anesthetic agents
Agent | Onset of action | pKa (36 °C) | Max dose (mg/kg)a | Duration of action (h) | |
|---|---|---|---|---|---|
Amides | Lidocaine | Rapid | 7.8 | 4.5 (7 with epi)
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